The present invention relates to novel semisynthetic macrolides having antibacterial activity and useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 6,11-4-carbon bridged erythromcyin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
Erythromycins A through D, represented by formula (E) as illustrated below, 
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Kashimura et al. have disclosed 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure in European Application 559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published Apr. 22, 1992.
Recently erythromycin derivatives containing a variety of substituents at the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549 and 6,075,011 as well as PCT Application WO00/78773. Furthermore, Ma, Or et. al. have described erythromycin derivatives with aryl groups tethered to the C-6 position in J. Med Chem., 44, pp 4137-4156 (2001). U.S. Pat. No. 6,046,171 and PCT application WO 99/21864, published May 6, 1999, disclose certain 6,11-bridged erythromycin derivatives.
The present invention provides a novel class of C6-C11 bridged macrolide compounds that possess antibacterial activity.
In one embodiment, the compounds of the present invention are represented by formula I, as illustrated below or their pharmaceutically acceptable salts, esters and prodrugs:: 
wherein
W is selected from the group consisting of:
(a) xe2x80x94CH2xe2x80x94C(A)xe2x95x90C(B)xe2x80x94CH2xe2x80x94;
xe2x80x83wherein,
A and B are independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) halogen;
(iv) R1, wherein R1 is selected from the group consisting of:
xe2x80x83a. C1-C6 alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
xe2x80x83b. C2-C6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
xe2x80x83c. C2-C6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(v) R2, wherein R2 is selected from the group consisting of:
xe2x80x83a. aryl;
xe2x80x83b. heteroaryl;
xe2x80x83c. substituted aryl; and
xe2x80x83d. substituted heteroaryl;
(vi) xe2x80x94(C1-C3-alkyl)-Mxe2x80x94(C1-C3-alkyl)-R2, wherein Mxe2x95x90xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, wherein n=0, 1 or 2, and R2 is as previously defined;
(vii) xe2x80x94(C1-C3-alkyl)-Mxe2x80x94R2, wherein M and R2 are as previously defined;
(viii) xe2x80x94C(O)xe2x80x94Jxe2x80x94R3, wherein J is absent, O or S, and R3 is H, R1 or R2, where R1 and R2 are as previously defined; and
(ix) xe2x80x94C(O)xe2x80x94NR11R12, wherein R11 and R12 are each independently selected from the group consisting of:
xe2x80x83a. hydrogen;
xe2x80x83b. C1-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
xe2x80x83c. C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
xe2x80x83d. C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of: halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
xe2x80x83e. R11 and R12 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of: xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(C1-C6-alkyl)-, xe2x80x94N(R2)xe2x80x94, xe2x80x94S(O)nxe2x80x94, wherein n and R2 are as previously defined;
(b) xe2x80x94CH2xe2x80x94CH(A)xe2x80x94C(B)xe2x95x90CHxe2x80x94, wherein A and B are as previously defined;
(c) xe2x80x94CH2xe2x80x94CH(E)xe2x80x94CH(G)xe2x80x94CH2xe2x80x94;
xe2x80x83wherein E and G are independently selected from the group consisting of:
(i) A, wherein A is as previously defined;
(ii) xe2x80x94OH;
(iii) xe2x80x94ORp, wherein Rp is a hydroxy protecting group;
(iv) xe2x80x94Oxe2x80x94R9, wherein R9 is R1 or R2, and wherein R1 and R2 are as previously defined;
(v) xe2x80x94S(O)nR9, wherein n and R9 are as previously defined;
(vi) xe2x80x94NHC(O)R3, wherein R3 is as previously defined;
(vii) xe2x80x94NHC(O)NR11R3, wherein R11 and R3 are as previously defined;
(viii) xe2x80x94NHS(O)2R9, wherein R9 is as previously defined;
(ix) xe2x80x94NHR13, wherein R13 is an amino protecting group; and
(x) xe2x80x94NR11R12, wherein R11 and R12 are as previously defined;
(d) 
xe2x80x83wherein:
(i) xe2x80x94Qxe2x80x94 is selected from the group consisting of: xe2x80x94Oxe2x80x94; xe2x80x94Oxe2x80x94C(O)xe2x80x94CH(R7)xe2x80x94; xe2x80x94N(R7)xe2x80x94; xe2x80x94Oxe2x80x94C(O)xe2x80x94N(R7)xe2x80x94; xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94; xe2x80x94N(R7)xe2x80x94Nxe2x95x90Nxe2x80x94; xe2x80x94C(R7)xe2x95x90Nxe2x80x94Oxe2x80x94; and CH(R7)xe2x80x94N(R8)xe2x80x94Oxe2x80x94; wherein R7 and R8 are independently selected from R3, wherein R3 is as previously defined; or
(ii) xe2x80x94Qxe2x80x94 taken together with the two carbon atoms it is attached to is selected from the group consisting of:
a. cycloalkylene;
b. cycloalkenylene; and
c. heterocycloalkylene; and
(e) xe2x80x94CH2xe2x80x94C(R4)(R5)xe2x80x94CH2xe2x80x94CH2xe2x80x94;
xe2x80x83wherein R4 and R5 taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) Cxe2x95x90O;
(ii) C(OR1)2, wherein R1 is as previously defined;
(iii) C(SR1)2, wherein R1 is as previously defined;
(iv) C[xe2x80x94O(CH2)m]2, wherein m is 2 or 3;
(v) C[xe2x80x94S(CH2)m]2, wherein m is as previously defined,
(vi) Cxe2x95x90CHR3, wherein R3 is as previously defined;
(vii) Cxe2x95x90Nxe2x80x94Oxe2x80x94R3, wherein R3 is as previously defined;
(viii) Cxe2x95x90NNHR3, wherein R3 is as previously defined;
(ix) Cxe2x95x90NNHC(O)R3, wherein R3 is as previously defined;
(x) Cxe2x95x90NNHC(O)NR11R3, wherein R11 and R3 are as previously defined;
(xi) Cxe2x95x90NNHS(O)2R9, wherein R9 is as previously defined;
(xii) Cxe2x95x90NNHR13, wherein R13 is as previously defined; and
(xiii) Cxe2x95x90NR9, wherein R9 is as previously defined;
X and Y are:
(a) independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) xe2x80x94OH;
(iv) ORp, wherein Rp is as previously defined; and
(v) xe2x80x94NR14R15, wherein R14 and R15 are each independently selected from the group consisting of:
a. hydrogen;
b. C1-C12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
c. R14 and R15, taken together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocycloalkyl ring optionally substituted with one or more hetero atoms selected from the group consisting of O, S and N; or
(b) taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) Cxe2x95x90O;
(ii) Cxe2x95x90NR3, wherein R3 is as previously defined;
(iii) Cxe2x95x90NC(O)R3, wherein R3 is as previously defined;
(iv) Cxe2x95x90Nxe2x80x94OR6, wherein R6 is selected from the group consisting of:
a. hydrogen;
b. xe2x80x94CH2O(CH2)2OCH3;
c. xe2x80x94CH2O(CH2O)nCH3, wherein n is as previously defined;
d. C1-C12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
e. C3-C12 cycloalkyl;
f. C(O)xe2x80x94C1-C12 alkyl;
g. C(O)xe2x80x94(C3-C12 cycloalkyl);
h. C(O)xe2x80x94R2, wherein R2 is as previously defined; and
i. xe2x80x94Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are each independently selected from the group consisting of C1-C12 alkyl, aryl and substituted aryl; and
(v) Cxe2x95x90Nxe2x80x94Oxe2x80x94C(R16)(R17)xe2x80x94Oxe2x80x94R18, wherein R16 and R17 taken together with the carbon atom to which they are attached form a C3 to C12 cycloalkyl group or each independently is selected from the group consisting of: hydrogen, and C1-C12 alkyl; and R18 is selected from the group consisting of:
a. hydrogen;
b. xe2x80x94CH2O(CH2)2OCH3;
c. xe2x80x94CH2O(CH2O)nCH3, wherein n is as previously defined;
d. C1-C12 alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
e. C3-C12 cycloalkyl; and
f. xe2x80x94Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are as previously defined;
L is selected from the group consisting of:
(a) xe2x80x94CH(OH)CH3;
(b) C1-C6 alkyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(c) C2-C6 alkenyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
(d) C2-C6 alkynyl, optionally substituted with one or more substituents selected from the group consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
K is selected from the group consisting of:
(a) R10, wherein R10 is selected from the group consisting of:
(i) hydrogen;
(ii) xe2x80x94ORp, wherein Rp is as previously defined;
(iii) xe2x80x94OR3, wherein R3 is as previously defined;
(iv) xe2x80x94OC(O)R3, wherein R3 is as previously defined;
(v) xe2x80x94OC(O)NR11R3, wherein R11 and R3 are as previously defined; and
(vi) xe2x80x94S(O)nR9, wherein n and R9 are as previously defined; and
(b) 
xe2x80x83wherein R3xe2x80x3 is hydrogen or methyl; R4xe2x80x3 is hydrogen or Rp, wherein Rp is as previously defined; and
Rx is hydrogen or Rp, wherein Rp is as previously defined.
In another aspect of the present invention, pharmaceutical compositions are disclosed that comprise a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier. The invention also includes a method of treatment of antibacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed. The compounds and compositions of the present invention have antibacterial activity. In a further aspect of the present invention, processes for the preparation of 6,11-4 carbon bridged macrolides of formula I are provided.
A first embodiment of the invention is a compound represented by formula I as illustrated above, or a pharmaceutically acceptable salt, ester or prodrug thereof.
A preferred group of compounds according to the present invention is represented by formula II as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein A, B, X, Y, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula III as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein A, B, X, Y, R10 and Rx are as previously defined.
Yet another preferred group of compounds according to the present invention is represented by formula IV as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein A, B, X, Y, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula V as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein A, B, X, Y, R10 and Rx are as previously defined.
Yet another preferred group of compounds according to the present invention is represented by formula VI as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein A, B, X, Y, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula VII as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein A, B, X, Y, R10 and Rx are as previously defined.
Yet another preferred group of compounds according to the present invention is represented by formula VIII as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein Q, X, Y, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula IX as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein Q, X, Y, R10 and Rx are as previously defined.
Yet another preferred group of compounds according to the present invention is represented by formula X as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein E, G, X, Y, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula XI as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein E, G, X, Y, R10 and Rx are as previously defined.
Yet another preferred group of compounds according to the present invention is represented by formula XII as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein X, Y, R4, R5, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula XIII as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein X, Y, R4, R5, R10 and Rx are as previously defined.
Yet another preferred group of compounds according to the present invention is represented by formula XIV as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein X, Y, R4, R5, Rx and R4xe2x80x3 are as previously defined.
Another preferred group of compounds according to the present invention is represented by formula XV as illustrated below, or a pharmaceutically acceptable salt, ester or prodrug thereof: 
wherein X, Y, R4, R5, R10 and Rx are as previously defined.
Another preferred embodiment of the invention are compounds represented by any of the above formulas I through XV wherein: X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of: Cxe2x95x90O, Cxe2x95x90NR3, Cxe2x95x90Nxe2x80x94Oxe2x80x94R6, Cxe2x95x90Nxe2x80x94C(O)R3 and Cxe2x95x90Nxe2x80x94Oxe2x80x94C(R16)(R17)xe2x80x94Oxe2x80x94R18 and RX is hydrogen, where R3, R6, R16, R17 and R18 are as previously defined.
Yet another preferred embodiment of the invention are compounds represented by any of the above formulas I through XV wherein: X and Y taken together with the carbon atom to which they are attached are selected from the group consisting of: Cxe2x95x90NC(O)R3 and Cxe2x95x90Nxe2x80x94Oxe2x80x94C(R16)(R17)xe2x80x94Oxe2x80x94R18; and RX is hydrogen, where R3 is methyl, R18 is methyl and R16 and R17 are each hydrogen.
Still yet another preferred embodiment of the invention are compounds represented by formula I wherein L is xe2x80x94CH2CH3xe2x80x94.
Another preferred embodiment of the invention are compounds represented by any of the above formulas III, V, VII, IX, XI, XIII and XV wherein R10xe2x95x90OH.
Representative compounds according to the invention include those selected from the group consisting of:
Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94OH; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94OH; Rx=H and R4xe2x80x3=C(O)CH3;
Compound of Formula (II): A=C(O)OCH3; B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94OH; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (VIII): Q=xe2x80x94C(C6H5)xe2x95x90Nxe2x80x94Oxe2x80x94; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (VIII): Q=xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (VIII): Q=xe2x80x94Oxe2x80x94; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (VIII): Q=xe2x80x94Oxe2x80x94; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=H;
Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90NC(O)CH2OCH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (II): A=B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)xe2x80x94CH2OCH3; Rx=H and R4xe2x80x3=H;
Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (IV): A=3-quinolyl; B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=H;
Compound of Formula (II): A=C(CHxe2x95x90CHxe2x80x94C6H5); B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (II): A=C(CHxe2x95x90CHxe2x80x94C6H5); B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90NC(O)CH3; Rx=H and R4xe2x80x3=H;
Compound of Formula (II): A=C(CHxe2x95x90CHxe2x80x94C6H5); B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94C(O)CH3; Rx=H and R4xe2x80x3=C(O)C6H5;
Compound of Formula (II): A=C(CHxe2x95x90CHxe2x80x94C6H5); B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90NC(O)CH3; Rx=H and R4xe2x80x3=H;
Compound of Formula (II): A=H; B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90N-Ac; Rx=H and R4xe2x80x3=H;
Compound of Formula (II): A=C(O)xe2x80x94OH; B=H; X and Y taken together with the carbon atom they are attached to=Cxe2x95x90Nxe2x80x94OH; Rx=H and R4xe2x80x3=H; and
Compound of Formula (II): A=B=H, X and Y taken together with the carbon atom they are attached to=Cxe2x95x90O, Rx=H and R4xe2x80x3=C(O)CH3.
Definitions
The terms xe2x80x9cC1-C3 alkyl,xe2x80x9d xe2x80x9cC1-C6 alkylxe2x80x9d or xe2x80x9cC1-C12 alkyl,xe2x80x9d as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals containing between one and three, one and twelve, or one and six carbon atoms, respectively. Examples of C1-C3 alkyl radicals include methyl, ethyl, propyl and isopropyl radicals; examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl and n-hexyl radicals; and examples of C1-C12 alkyl radicals include, but are not limited to, ethyl, propyl, isopropyl, n-hexyl, octyl, decyl, dodecyl radicals.
The term xe2x80x9csubstituted alkylxe2x80x9d or xe2x80x9calkyl substituentxe2x80x9d refers to an alkyl group substituted by, for example, one to four substituents, such as, halo, phenyl, substituted phenyl, heterocyclo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyoxy, heterocylooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkysulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidine and heterocyclos, such as, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, and the like. Where, if noted above, the substituent is further substituted, it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl.
The term xe2x80x9calkylenexe2x80x9d denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example, methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, and the like.
The terms xe2x80x9cC2-C12 alkenylxe2x80x9d or xe2x80x9cC2-C6 alkenyl,xe2x80x9d as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon double bond by the removal of a single hydrogen atom. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The term xe2x80x9calkenylenexe2x80x9d denotes a divalent group derived from an alkenyl group as defined previously by the removal a second hydrogen atom, containing from two to twelve carbon atoms and having at least one carbon-carbon double bond, for example, 1,2-ethenyl, 1,2-propylene, 1,4-butenyl, 1-methyl-but-1-en-1,4-yl, and the like.
The terms xe2x80x9cC2-C12 alkynylxe2x80x9d or xe2x80x9cC2-C6 alkynyl,xe2x80x9d as used herein, denote a monovalent group derived from a hydrocarbon moiety containing from two to twelve or two to six carbon atoms having at least one carbon-carbon triple bond by the removal of two hydrogen atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogen,xe2x80x9d as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term xe2x80x9chaloalkylxe2x80x9d denotes an alkyl group, as defined above, having one, two or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substitutents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9carylenexe2x80x9d denotes a divalent group derived from an aryl moiety as defined previously by the removal of a second hydrogen atom. Arylene groups include, for example, 1,2-phenyl, 1,3-phenyl, 1,4-phenyl, 1,2-naphthyl, 1,4-naphthyl, 1,6-naphthyl, and the like.
The term xe2x80x9csubstituted aryl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO2, CN, C(O)xe2x80x94C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2-alkyl, CO2-aryl, CO2-heteroaryl, CONH2, CONHxe2x80x94C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)xe2x80x94C1-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO2-alkyl, OCO2-aryl, OCO2-heteroaryl, OCONH2, OCONHxe2x80x94C1-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)xe2x80x94C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO2-alkyl, NHCO2-aryl, NHCO2-heteroaryl, NHCONH2, NHCONHxe2x80x94C1-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO2xe2x80x94C1-C6-alkyl, SO2-aryl, SO2-heteroaryl, SO2NH2, SO2NHxe2x80x94C1-C6-alkyl, SO2NH-aryl, SO2NH-heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHCl2, CH2OH, CH2CH2OH, CH2NH2, CH2SO2CH3, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-alkylamino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-C6-alkyl-thio, or methylthiomethyl.
The term xe2x80x9csubstituted arylenexe2x80x9d as used herein refers to an arylene group as defined herein substituted by independent replacement of one, two or three of the hydrogen atoms thereon with halo, hydroxyl, cyano, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, mercapto, nitro, carboxaldehyde, carboxyl, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group. Also, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to a cyclic aromatic radical having from five to ten ring atoms of which one ring atom is selected from S, O and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.
The term xe2x80x9cheteroarylenexe2x80x9d denotes a divalent group derived from a heteroaryl moiety as defined previously by the removal a second hydrogen atom. Heteroarylene groups include, for example, 2,3-pyridyl, 2,4-pyridyl 2,6-pyridyl, 2,3-quinolyl, 2,4-quinolyl, 2,6-quinolyl, 1,4-isoquinolyl, 1,6-isoquinolyl, and the like.
The term xe2x80x9csubstituted heteroaryl,xe2x80x9d as used herein, refers to a heteroaryl group as defined herein, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO2, CN, C(O)xe2x80x94C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO2-alkyl, CO2-aryl, CO2-heteroaryl, CONH2, CONHxe2x80x94C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)xe2x80x94C1-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCO2-alkyl, OCO2-aryl, OCO2-heteroaryl, OCONH2, OCONHxe2x80x94C1-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)xe2x80x94C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO2-alkyl, NHCO2-aryl, NHCO2-heteroaryl, NHCONH2, NHCONHxe2x80x94C1-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO2-C1-C6-alkyl, SO2-aryl, SO2-heteroaryl, SO2NH2, SO2NHxe2x80x94C1-C6-alkyl, SO2NH-aryl, SO2NH-heteroaryl, C1-C6-alkyl, C3-C6-cycloalkyl, CF3, CH2CF3, CHCl2, CH2OH, CH2CH2OH, CH2NH2, CH2SO2CH3, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-C6-alkyl-thio, or methylthiomethyl.
The term xe2x80x9csubstituted heteroarylene,xe2x80x9d as used herein, refers to a heteroarylene group as defined herein substituted by independent replacement of one, two or three, of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and the like. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term xe2x80x9cC3-C12-cycloalkylxe2x80x9d or xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound by the removal of a single hydrogen atom. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
The term xe2x80x9cheterocycloalkyl,xe2x80x9d as used herein, refers to a non-aromatic 3- to 7-membered ring or a bi- or tri-cyclic group comprising fused six-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to a benzene ring. Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term xe2x80x9ccycloalkylenexe2x80x9d refers to a divalent cycloalkyl moiety with two hydrogen atoms removedxe2x80x94one each from two adjacent carbon atomsxe2x80x94derived by the removal of the two hydrogen atoms from a cycloalkyl group as previously defined that is optionally substituted, or from saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused to an unsaturated C3-C7 carbocyclic ring. Exemplary cycloalkyl groups from which the cycloalkylene groups can be derived include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantly. Exemplary substituents include one or more alkyl, aryl, heteroaryl groups as described above, or one or more groups described above as alkyl substituents.
The term xe2x80x9ccycloalkenylenexe2x80x9d refers to a divalent cycloalkenyl moiety with two hydrogen atoms removedxe2x80x94one each from two adjacent carbon atomsxe2x80x94derived by the removal of the two hydrogen atoms from a cycloalkenyl group that contains one or more unsaturated double bonds optionally substituted, or from unsaturated cyclic ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary cycloalkenyl groups from which the cycloalkenylene groups can be derived include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like. Exemplary substituents include one or more alkyl, aryl, heteroaryl groups as described above, or one or more groups described above as alkyl substituents.
The term xe2x80x9cheterocycloalkylenexe2x80x9d refers to a divalent heterocyclic moiety with two hydrogen atoms removedxe2x80x94one each from two adjacent carbon atomsxe2x80x94derived by the removal of the two hydrogen atoms from a heterocycloalkyl group previously defined that is optionally substituted, or from a fully saturated or unsaturated, nonaromatic cyclic group which may be further fused with or substituted with an aromatic ring, for example, which is a 3 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom. Exemplary monocyclic heterocyclic groups from which the heterocycloalkylene groups can be derived include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like. Exemplary bicyclic heterocyclic groups from which the heterocycloalkylene groups can be derived include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazollinyl, (such as 3,4-dihydro-4-oxo-quiazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like. Exemplary substituents include one or more alkyl, aryl or heteroaryl groups as described above or one or more groups described above as alkyl substituents. Also included are smaller heterocyclics, such as epoxides and aziridines.
The term xe2x80x9cheteroatomsxe2x80x9d includes, but is not limited to, oxygen, sulfur and nitrogen.
The term xe2x80x9cC1-C6 alkoxy,xe2x80x9d as used herein, refers to a C1-C6 alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and n-hexoxy.
The term xe2x80x9cC1-C3-alkyl-amino,xe2x80x9d as used herein, refers to one or two C1-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of C1-C3-alkyl-amino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
The term xe2x80x9calkylaminoxe2x80x9d refers to a group having the structure xe2x80x94NH(C1-C12 alkyl) where C1-C12 alkyl is as previously defined.
The term xe2x80x9cdialkylaminoxe2x80x9d refers to a group having the structure xe2x80x94N(C1-C12 alkyl)(C1-C12 alkyl), where C1-C12 alkyl is as previously defined. Examples of dialkylaminoinclude, but are not limited to, dimethylamino, diethylamino, methylethylamino, piperidino, and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d represents an ester group, i.e. an alkoxy group, attached to the parent molecular moiety through a carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the like.
The term xe2x80x9ccarboxaldehyde,xe2x80x9d as used herein, refers to a group of formula xe2x80x94CHO.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a group of formula xe2x80x94COOH.
The term xe2x80x9ccarboxamide,xe2x80x9d as used herein, refers to a group of formula xe2x80x94C(O)NH(C1-C12 alkyl) or xe2x80x94C(O)N(C1-C12 alkyl)(C1-C12 alkyl).
xe2x80x9cHydroxy protecting group,xe2x80x9d as used herein, refers to an easily removable group such as is known in the art to protect a hydroxy group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999). Examples of hydroxy protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group and the like.
The term xe2x80x9cprotected hydroxyxe2x80x9d refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
xe2x80x9cAmino protecting group,xe2x80x9d as used herein, refers to an easily removable group such as is known in the art to protect an amino group against undesirable reaction during synthetic procedures and to be selectively removable. The use of amino-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, 9-fluorenylmethyl carbamate, benzylcarbonate, tert-butylcarbonate, benzyl, p-toluene sulfonyl, acyl and the like.
The term xe2x80x9caprotic solvent,xe2x80x9d as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley and Sons, NY, 1986.
The term xe2x80x9cprotic solventxe2x80x9d or xe2x80x9cprotogenic organic solvent,xe2x80x9d as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley and Sons, NY, 1986.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term xe2x80x9cpharmaceutically acceptable esterxe2x80x9d refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed from the compounds of the present invention.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention. The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussions is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., xe2x80x9cBioreversible Carriers in Drug Designxe2x80x9d, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H. Bundgaard, p. 113-191 (1991);
c) H. Bundgaard, et al., Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1998); and
e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984).
It should further be understood that solvates (e.g., hydrates) of the compounds of the present invention are also within the scope of the present invention. Methods of solvation are generally known in the art.
Antibacterial Activity
Susceptibility tests can be used to quantitatively measure the in vitro activity of an antimicrobial agent against a given bacterial isolate. Compounds were tested for in vitro antibacterial activity by a micro-dilution method. Minimal Inhibitory Concentration (SC) was determined in 96 well microtiter plates utilizing the appropriate Mueller Hinton Broth medium (CAMHB) for the observed bacterial isolates. Antimicrobial agents were serially diluted (2-fold) in DMSO to produce a concentration range from about 64 xcexcg/ml to about 0.03 xcexcg/ml. The diluted compounds (2 xcexcl/well) were then transferred into sterile, uninoculated CAMHB (0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculum for each bacterial strain was standardized to 5xc3x97105 CFU/mL by optical comparison to a 0.5 McFarland turbidity standard. The plates were inoculated with 10 xcexcl/well of adjusted bacterial inoculum. The 96 well plates were covered and incubated at 35+/xe2x88x922xc2x0 C. for 24 hours in ambient air environment. Following incubation, plate wells were visually examined by Optical Density measurement for the presence of growth (turbidity). The lowest concentration of an antimicrobial agent at which no visible growth occurs was defined as the MIC. The compounds of the invention generally demonstrated an MIC in the range from about 64 xcexcg/ml to about 0.03 xcexcg/ml.
All in vitro testing follows the guidelines described in the Approved Standards M7-A4 protocol, published by the National Committee for Clinical Laboratory Standards (NCCLS).
Pharmaceutical Compositions
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer""s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate. Coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringees solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or other animals by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment of from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
The pharmaceutical compositions of this invention can be administered to fish by blending them in the fish feed to be administered orally or may be dissolved in water in which sick fish are placed to swim around (a method using a so-called xe2x80x9cmedicated bathxe2x80x9d). The dosage for the treatment of fish differs depending upon the purpose of administration (prevention or cure of disease) and type, size and extent of infection of the fish to be treated. Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kg of body weight of fish may be administered per day, either at one time or divided into several times. It will be recognized that the above-specified dosage is only a general range which may be reduced or increased depending upon the age, body weight, condition of disease, etc. of the fish.
Abbreviations
Abbreviations which have been used in the description of the schemes and the examples are as follows: AIBN for azobisisobutyronitrile; Boc for tert-Butoxycarbonyl; BSA for bis(trimethylsilyl)acetamide; Bu3SnH for tributyltin hydride; CDI for carbonyldiimidazole; dba for dibenzylideneacetone; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP for 4-N,N-dimethylamino-pyridine; DCC for 1,3-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DMF for dimethyl formamide; DMSO for dimethylsulfoxide; DPPA for diphenylphosphoryl azide; dppb for 1,4-bis(diphenylphosphino)butane; dppe for 1,2-bis(diphenylphosphino)ethane; EDC for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EtOAc for ethyl acetate; HMDS for 1,1,1,3,3,3-Hexamethyldisilazane; KHMDS for potassium bis(trimethylsilyl)amide; m-CPBA for meta-chloroperbenzoic acid; MeOH for methanol; MOMCl for methoxymethylchloride; NaHMDS for sodium bis(trimethylsilyl)amide; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NCS for N-Chlorosuccinimide; NMO for N-methylmorpholine N-oxide; PCC for pyridinium chlorochromate; PDC for pyridinium dichromate; Ph for phenyl; TBS for tert-butyl dimethyl silyl; TEA for triethylamine; THF for tetrahydrofuran; TPP for triphenylphosphine; TBAF for tetra-n-butyl ammonium fluoride; TFA for trifluoroacetic acid; TMS for trimethyl silyl; TPAP for tetrapropylammonium perruthenate; Ac for acetyl and Bz for benzoyl.
Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes (schemes 1-12) that illustrate the methods by which the compounds of the invention may be prepared. The groups A, B, Rx, R3, R6, Rp, X and Y are as defined previously herein, unless otherwise noted below. As used in the schemes and examples, the group xe2x80x9cVxe2x80x9d taken together with the carbon atom it is attached to is selected from the group: Cxe2x95x90O, Cxe2x95x90NR3, Cxe2x95x90Nxe2x80x94Oxe2x80x94R6, Cxe2x95x90NC(O)R3 and Cxe2x95x90Nxe2x80x94Oxe2x80x94C(R16)(R17)xe2x80x94Oxe2x80x94R18, where R3, R6, R16, R17 and R18 are as previously defined herein.
Compounds of formula (1-2) or (1-4), which are useful as the starting materials for the preparation of compounds of the present invention, may be synthesized as detailed in schemes 1 and 3 below. An eryromycin derivative (1-1) is prepared from erythromycin using the procedures described in U.S. Pat. Nos. 4,990,602; 4,331,803; 4,680,386; and 4,670,549 which are incorporated herein by reference. Also incorporated by reference is European Patent Application EP 260,938. The procedures for preparing the 6,11-bridged compounds of the present invention are described in U.S. patent application Ser. Nos. 10/144,396 and 10/144,558, filed on May 13, 2002, which are herein incorporated by reference in their entirety. The C-9 position (X, Y) can be further derivatized with suitable procedures that are well-known in the art and those mentioned in PCT publications: WO 00/62783 and WO 98/38199 as well as publications: xe2x80x9cSynthetic Modifications of the Erythromycin A Macrolactone: Effects on Biological Activity,xe2x80x9d Lartey, P. A. and Perun, T. J., Atta-ur-Rahman (Ed.) Studies in Natural Products Chemistry, Vol. 13, 1993, and xe2x80x9cRecent developments in 14- and 15-membered macrolides,xe2x80x9d Chu, Daniel T. W., Section Review: Anti-infectives, Exp. Opin. Invest. Drugs 1995, 4(2), page 65-94, which are herein incorporated by reference in their entirety.
A preferred intermediate for the preparation of compounds represented by formula I is a compound represented by formula XVI as illustrated below: 
wherein R6 and Rx are as previously defined and R4xe2x80x3 is a hydroxy protecting group.
A second preferred intermediate for the preparation of compounds represented by formula I is a compound represented by formula XVII as illustrated below: 
wherein A, B, Rx and R4xe2x80x3 are as previously defined; V taken together with the carbon atom it is attached to is selected from the groups: Cxe2x95x90O, Cxe2x95x90NR3, Cxe2x95x90Nxe2x80x94Oxe2x80x94R6, Cxe2x95x90NC(O)R3 and Cxe2x95x90Nxe2x80x94Oxe2x80x94Oxe2x80x94C(R16)(R17)xe2x80x94Oxe2x80x94R18, where R3, R6, R16, R17 and R18 are as previously defined; and RP1 is H or RP, where RP is as previously defined. 
A synthetic method of the present invention, as illustrated in scheme 1, involves preparing a compound of formula (1-4) by reacting a compound of formula (1-2) with a suitable alkylating agent.
In accordance with scheme 1, the 9-keto group of the erythromycin backbone can be initially converted into an oxime by methods described in U.S. Pat. No. 4,990,602, followed by the protection of the 2xe2x80x2- and 4xe2x80x3-hydroxy groups with Rx and R4xe2x80x3 respectively, and if desired, the resulting oxime group can be further derivatized with R6 to obtain the compounds of formula (1-2).
The 2xe2x80x2- and 4xe2x80x3-hydroxy groups are protected by reaction with suitable hydroxy protecting agents in an aprotic solvent. Typical hydroxy protecting reagents include, but are not limited to, acetylating agents, silylating agents, acid anhydrides, and the like. Examples of hydroxy protecting reagents are, for example, acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, benzyl chloroformate, hexamethyldisilazane, and trialkylsilyl chlorides.
Examples of aprotic solvents are dichloromethane, chloroform, tetrahydrofuran, N-methylpyrrolidinone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents with ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-dichloroethane, acetonitrile, ethyl acetate, acetone and the like. Aprotic solvents do not adversely affect the reaction. Preferably, the solvent is selected from dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidinone or mixtures thereof. A more thorough discussion of solvents and conditions for protecting the hydroxy group can be found in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 3rd ed., John Wiley and Son, Inc, 1999, which is incorporated by reference herein.
Protection of the 2xe2x80x2- and 4xe2x80x3-hydroxy groups may be accomplished sequentially or simultaneously to provide compound (1-2) where Rx and/or R4xe2x80x3 can be, for example, but not limited to, acetyl, benzoyl, trimethylsilyl, and the like. Preferred protecting groups include acetyl, benzoyl, and trimethylsilyl. A particularly preferred group for protecting the hydroxy and oxime groups is the acetyl protecting group, wherein Rx=R4xe2x80x3=R6=Ac.
Acetylation of the hydroxy group is typically accomplished by treating the compound (1-1) with an acetylating reagent, for example, acetic anhydride or acetyl chloride.
The erythromycin derivative of formula (1-2) is then reacted with an alkylating agent of the formula: 
where R19 is C1-C12-alkyl.
The reaction is carried out in an aprotic solvent with a palladium catalyst [Pd(0) or Pd(II)] with a phosphorus ligand such as, for example, dppb, dppe, and the like, in aprotic solvents to provide compound (1-4) from about room temperature to about 100xc2x0 C., preferably at elevated temperature, for example, at or above 50xc2x0 C. (see (a) Trost, B. M. Angew. Chem. Int. Ed. Eng. 1989, 28, 1179; (b) Heck, Palladium Reagents in Organic Synthesis, Academic Press: New York, 1985, Chapter 1; (c) Tsuji, Tetrahedron Lett. 1992, 33, 2987; (d) Beller et al. Angew. Chem. Int. Ed. Engl., 1995, 34 (17), 1848, etc.). Suitable aprotic solvents include, but are not limited to, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, 1,2-dimethoxyethane, methyl-tert-butyl ether, heptane, acetonitrile, isopropyl acetate and ethyl acetate. The most preferred solvents are tetrahydrofuran or toluene.
The palladium catalyst suitable in the present invention can be selected from, but not limited to, the group consisting of palladium (II) acetate, tetrakis(triphenylphosphine) palladium (0), tris(dibenzylideneacetone)dipalladium, tetradi(benzylideneacetone)dipalladium and the like. Palladium on carbon and palladium (II) halide catalysts are less preferred than other palladium catalysts for this process.
Phosphorus ligands useful in the present invention include, but are not limited to, triphenylphosphine, bis(diphenylphosphino)methane, bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, bis(diphenylphosphino)pentane, and tir(o-tolyl)phosphine, and the like.
The alkylating agents useful in the present invention are dicarbonates having the formula (1-3), as previously described. The preferred alkylating agents are those wherein R19 is a tert-butyl, isopropyl or isobutyl group. The alkylating reagents are prepared by reaction of a di-ol with a wide variety of compounds for incorporating the di-carbonate moiety. The compounds include, but are not limited to, tert-butyl chloroformate, di-tert-butyl dicarbonate, 1-(tert-butoxycarbonyl)imidazole etc. The reaction is carried out in the presence of an organic or an inorganic base such as, for example, but not limited to, sodium hydride, potassium hydride, potassium tert-butoxide, potassium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, ammonium carbonate, KHMDS, DMAP, pyridine, triethylamine, and the like, in an aprotic solvent such as THF, DMSO, DMF, dioxane, and the like, or mixtures thereof. The temperature for the reaction ranges from about xe2x88x9220xc2x0 C. to about 60xc2x0 C., preferably from about xe2x88x9230xc2x0 C. to about 30xc2x0 C.
The conversion of the di-ol into the di-carbonate can also be done by treating the di-ol with phosgene or triphosgene to prepare the chloroformate derivative of the di-ol. The di-chloroformate derivative is then converted into the di-carbonate by the methods described in Cotarca, L., Delogu, P., Nardelli, A., Sunijic, V, Synthesis, 1996, 553, incorporated by reference herein in its entirety. The reaction can be carried out in a variety of organic solvents such as dichloromethane, toluene, diethyl ether, ethyl acetate, chloroform, and the like, in the presence of a base as previously described herein. The temperature conditions can vary from about xe2x88x9230xc2x0 C. to about 60xc2x0 C. The reaction takes from about 1 hour to about 12 hours, preferably from about 2 to about 6 hours, to run to completion. 
The cladinose moiety of macrolide (1-4) is removed by mild acid hydrolysis to give compounds of formula (2-1). Representative acids include, but are not limited to, hydrochloric acid, sulfuric acid, perchloric acid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, and the like. Suitable solvents for the reaction include, but are not limited to, methanol, ethanol, isopropanol, butanol and the like. Reaction times range from about 0.5 hours to about 24 hours. The reaction temperature is preferably from about xe2x88x9210xc2x0 C. to about 80xc2x0 C. Simultaneous deprotection, of both the oxime and the 2xe2x80x2 hydroxy group, can be accomplished similarly.
Conditions for deprotection include, but are not limited to, treating with an alcoholic solvent from room temperature to reflux, or treatment with an amine, preferably a primary amine, for example, propylamine, butylamine, and the like. Alcoholic solvents preferred for the deprotection are methanol and ethanol. A more thorough discussion of the procedures, reagents and conditions for removing protecting groups is described in the literature, for example, by T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 3rd ed., John Wiley and Son, Inc, 1999, which is incorporated by reference herein. 
Compounds of formula (1-4) where R is an acetyl group can be converted into the corresponding imine as outlined in Scheme 3. Selective deprotection of the oxime is typically accomplished via alkaline hydrolysis in protic solvents. Representative bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like. Solvents which are suitable include, but are not limited to, tetrahydrofuran, 1,4dioxane, 1,2-dimethoxyethane, isopropanol, ethanol, butanol, water and mixtures thereof. The reaction temperature is preferably 0xc2x0 to 35xc2x0 C., and reaction time is preferably 0.5 to 24 hours.
Deoximation of compounds of formula (1-4) where R6 is H can be done under reducing conditions to give the macrolide imine of formula (3-2). Many reducing agents can be used to effect this transformation including, but not limited to, lithium aluminum hydride, titanium trichloride, sodium cyanoborohydride, borane, sodium nitrite, sulfur oxides such as, for example, sodium pyrosulfate, sodium thiosulfate, sodium sulfate, sodium sulfite, sodium hydrogensulfite, sodium metabisulfite, sodium dithionate, potassium thiosulfate, potassium metabisulfite, and the like (also see, (a) Greene (op. cit.); (b) J. March, Advanced Organic Chemistry, 4th ed., Wiley and Son, Inc., 1992, 9-51, and references therein). For example, when appropriate the reaction is carried out under acidic conditions in protic solvents. Representative acids include, but are not limited to, acetic acid, citric acid, oxalic acid, tartaric acid, formic acid, dilute hydrochloric acid, dilute phosphoric acid, dilute sulfuric acid, and the like. Suitable protic solvents include, but are not limited to, mixtures of water and methanol, ethanol, isopropanol, butanol etc. The reaction is carried out at a temperature from about room temperature to about 110xc2x0 C., for about 1 to about 24 hours.
An example of a method for the reduction of oximes to the corresponding imine uses a sulfite reducing agent such as sodium hydrogensulfite or titanium trichloride, under acidic conditions in protic solvents. Representative acids that may be used include, but are not limited to, acetic acid, formic acid, dilute hydrochloric acid, dilute phosphoric acid, dilute sulfuric acid, and the like. Suitable protic solvents include, but are not limited to, mixtures of water and methanol, ethanol, isopropanol, or butanol. The reaction is typically carried out from about 25xc2x0 C. to about 110xc2x0 C., preferably for about 1 to about 10 hours. 
Another method of the present invention, as illustrated in Scheme 4, involves a procedure for the acylation of imines of the formula (3-2). The imine in the 9 position of compounds of formula (3-2) can be acylated with an acylating agent such as, for example, R3C(O)T, where T is a halide or xe2x80x94OH, or (R3C(O))2O, where R3 is as previously defined using standard acylating conditions to give compounds of formula (4-1). For example, imines of formula (3-2) can be acylated under basic conditions using a suitable acylating agent in an aprotic solvent, with or without an activation agent. Typical acylating agents include, but are not limited to, acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, benzyl chloroformate, and the like. Examples of activation agents for acids include, but are not limited to, DCC, EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc.
Typical bases useful in acylation reactions include, but are not limited to, pyridine, DMAP, triethylamine, diisopropyl ethylamine, N-methyl morpholine, N-methyl pyrrolidine, 2,6-lutidine, 1,8diazabicyclo[5.4.0]undec-7-ene, and the like (see, T. W. Greene and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 3rd ed., John Wiley and Son, Inc, 1999, and references therein). Compounds of formula (2-3) can be further deprotected as described in scheme 1 to obtain the 2xe2x80x2 free hydroxy group and the 9-position oxime. 
Stepwise formation of the 6,11-4-carbon bridged macrolides is also possible as outlined in scheme 5. In a similar manner as previously described, the procedure involves reacting a compound of formula (1-2) with a suitable alkylating agent. As before, the erythromycin derivative of formula (1-2) is reacted with an alkylating agent of the formula: 
where R19 is C1-C12-alkyl and A and B are as previously defined and Rp1 is H or RP where RP is as previously defined.
As discussed previously in scheme 1, compounds of formula (1-2) may be converted to compounds of formula (5-2) using a palladium catalyst with a phosphorous ligand in an aprotic solvent, preferably at elevated temperature, more preferably at or above 50xc2x0 C. The preferred solvents are tetrahydrofuran and toluene.
The alkylating agents useful in the process of the invention are mixed silyl ether carbonates. Generally, the alkylating agents have the formula (5-1), as previously described. The preferred alkylating agents are those wherein R19 is tert-butyl, isopropyl or isobutyl and Rp is tert-butyl dimethyl silyl, triisopropyl silyl, tert-butyl diphenyl silyl or the like.
The alkylating reagents of formula (5-1) are prepared by reaction of a diol sequentially with a wide variety of compounds for incorporating the carbonate moiety, followed by a wide variety of compounds for incorporating the silyl moiety. Alkylating reagents include, but are not limited to, tert-butyl chloroformate, di-tert-butyl dicarbonate, and 1-(tert-butoxycarbonyl)imidazole; where as silylating reagents include, but are not limited to tert-butyl dimethyl silyl chloride, tert-butyl dimethyl silyl triflate, tert-butyl dimethyl silyl cyanide, and tert-butyl dimethyl silyl imidazole. Both reactions are carried out in the presence of an organic or an inorganic base as previously described in scheme 1. The temperature of the reactions varies from about xe2x88x9230xc2x0 C. to about 60xc2x0 C. Preferably, the alkylating reagent is di-tert-butyl dicarbonate and the silylating reagent is tert-butyl dimethyl silyl chloride.
The free oxime (5-3) is prepared using essentially the same procedure as for the deprotection of oxime (1-4) to (3-1) where R6 is acetyl in scheme 1.
Reduction of oximes of formula (5-3) to the corresponding ketone compounds of formula (5-4) may be done by, for example, but not limited to, using a sulfite reducing agent, such as sodium hydrogensulfite, under acidic conditions, typically in protic solvents, as previously described for the reduction of oximes of formula (3-1) to compounds of formula (3-2). Representative acids include, but are not limited to, acetic acid, formic acid, dilute hydrochloric acid, dilute phosphoric acid, dilute sulfuric acid, and the like. Suitable protic solvents include, but are not limited to, mixtures of water and methanol, ethanol, isopropanol, or butanol. The reaction is typically carried out at a temperature from about 50xc2x0 C. to about 110xc2x0 C., preferably for about 1 to about 10 hours.
When the Rp1 group is RP (i.e., a hydroxy protecting group) in a compound of formula (5-4) then the hydroxy protecting group is removed using appropriate conditions. For example, when the protecting group is a silyl group, TBAF, hydrofluoric acid or trifluoroacetic acid may be used (see, T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis 3rd ed., John Wiley and Son, Inc, 1999). The resulting primary hydroxy group (where Rp1=H) is converted to the corresponding tert-butyl carbonate by standard methods known in the art, followed by alkylation of the 11-hydroxy group using a palladium (0) catalyst as previously described in scheme 1, to form compounds of formula (5-6). 
Scheme 6 illustrates a procedure for the acylation of the C-3 hydroxy group of compounds of formula (6-1). The C-3 hydroxy group is acylated under basic conditions using a suitable acylating agent to introduce the acyl group of the formula xe2x80x94C(O)xe2x80x94Zxe2x80x94R2, where Z is O, N, S or xe2x80x94(CH2)t, where t=0 to 4 and R2 is as previously described, in an aprotic solvent as previously described for acylating compounds of formula (3-2). Typical acylating agents include, but are not limited to, acid halides, acid anhydrides, free acids and chloroformates. Typical bases include, but are not limited to, pyridine, DMAP, triethylamine, diisopropyl ethylamine, N-methyl morpholine, N-methyl pyrrolidine, 2,6-lutidne, 1,8-diazabicyclo[5.4.0]undec-7-ene. (See, T. W. Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis 3rd ed., John Wiley and Son, Inc, 1999, and references therein).
Alternately, in compounds of formula (6-1) the C-3 hydroxy group may be further derivatized to form, for example, ethers, esters, sulfonates, and the like, using methods well known in the art (see, for example, J. March, Advanced Organic Chemistry 4th ed., Wiley and Son, Inc., 1992; and the references therein). 
Another method of the present invention, as illustrated in Scheme 7, involves synthesis of the C-3 deoxygenated macrolide (7-2) which can be accomplished via the two step procedure shown above. In the first step, the xanthate or thiocarbonate of formula (7-1) is formed by the reaction of alcohol of formula (6-1) with the appropriate thiocarbonyl compound. These reactions are typically run in a polar aprotic solvent, preferably tetrahydrofuran, acetonitrile, N,N-dimethylformamide, and the like. Formation of the xanthate can be accomplished, for example, by reaction of the alcohol (6-1) with, for example, but not limited to, carbondisulfide followed by methyliodide, or a dithiocarbonyl imidazole etc. The thiocarbonate can be prepared by the reaction of the alcohol with for example, but not limited to, thiocarbonyldimidazole followed by methanol, ethanol or the like, or a thiochloroformate etc. One skilled in the art will appreciate that other reagents and conditions exist to perform these transformations and that the examples above are for illustrative purposes only and do not limit the scope of this invention.
In the second step, the thiocarbonate or xanthate of formula (7-1) is converted to compound (7-2). Most typically this is done under radical conditions using, for example, a silyl hydride such as SiH(TMS)3, SiH2Ph2 or the like, a tin hydride such as Bu3SnH, Ph3SnH or the like, and a radical initiator such as AIBN or t-butyl peroxide. The preferred solvent is toluene. 
Compounds according to the formula (6-2) may be prepared from compounds of formula (6-1) by selective hydrogenation methods known in the art, for example, but not limited to, metal hydrides, such as, borane, or hydrogen in the presence of a catalyst, such as, palladium-on-charcoal, platinum metal or oxide, Wilkinson""s catalyst and the like (see, Rylander, Hydrogenation Methods; Academic Press: New York, 1985; J. March, Advanced Organic Chemistry 4th ed., Wiley and Son, Inc., 1992; and the references therein). 
Compounds (9-1, 9-2 and 9-3, where R is R3as previously defined herein) can be prepared by the well-established 1,3-dipolar cycloaddition reactions, such as, but not limited to, reaction of compound (6-1) and an oxime in the presence of NCS in an aprotic solvent such as ethyl acetate, methylene chloride, THF, or the like, to form compound (9-1) (see (a) Tufariello, Joseph J. Nitrones in 1,3 [One,Three]-Dipolar Cycloaddit. Chem. (1984), 2, 83-168. (b) Huisgen, Rolf. 1,3-Dipolar cycloadditionxe2x80x94introduction, survey, mechanism in 1,3 [One,Three]-Dipolar Cycloaddit. Chem. (1984), 1, 1-176, and the references therein). Compounds (9-2) and (9-3) can be prepared similarly by reacting compound (9-1) with an azide or a nitrone respectively.
Other 1,3-Dipolar cycloaddition reactants useful in forming cycloaddition products with compounds of the present invention such as compound (6-1) include, but are not limited to, diazoalkane, nitrous oxide, nitrile imine, nitrile ylide, nitrile oxide, etc. (see, Padwa 1,3-Dipolar Cycloaddition Chemistry, 2 vols.; Wiley: New York, 1984, and J. March, Advanced Organic Chemistry, 4th edition; Wiley: New York, 1992, and the references therein). 
Compound (10-1) is prepared by Diels-Alder reactions, where Ry and Rz are for example, but not limited to, CHO, COOH, COOR, COR, COAr, CN, NO2, Ar, CH2OH, CH2Cl, CH2NH2, CH2CN, CH2COOH, halogen, xe2x80x94Cxe2x95x90Cxe2x80x94, R and the like, R being R3 as previously defined herein (see (a) Danishefsky, Samuel. Cycloaddition and cyclocondensation reactions of highly functionalized dienes: applications to organic synthesis in Chemtracts: Org. Chem. (1989), 2 (5), 273-97, (b) Larock Comprehensive Organic Transformation; VCH: New York, 1989, 263-272, and the references therein).
Aziridines such as compound (10-2) can be obtained from, for example, but not limited to, the reaction of compound (6-1) with iodine in the presence of a primary amine in an aprotic solvent such as methylene chloride, THF, and the like.
Lactones such as compound (10-3) can be obtained by a variety of reactions such as but not limited to, reaction with: manganese (III) acetate in the presence of acetic acid, lead tetraacetate, xcex1-bromocarboxylic acids in the presence of benzoyl peroxide etc. (see, Larock Comprehensive Organic Transformation; VCH: New York, 1989; J. March, Advanced Organic Chemistry, 4th edition; Wiley: New York, 1992, and the references therein). 
Compound (11-1) is prepared by osmium tetraoxide (OsO4) catalyzed dihydroxylation of the double bond. In a typical procedure, compound (6-1) is treated with about 1 to about 3 equivalents of NMO in a solvent like t-butanol or acetone, with or without water, in the presence of about 1 to about 10% of OsO4. Compound (11-2) can then be obtained from compound (11-3) through standard acylation or alkylation of the diol, where R7 and R8 are independently selected from R3 and where R3 is as previously defined herein.
Compound (11-3) is prepared by epoxidation of the double bond with reagents such as, but not limited to, peracids, e.g. m-CPBA, hydrogen peroxide, t-BuOOH etc. (see (a) Chem. Rev. 1989, 89, 431; (b) Chem. Rev. 1992, 92, 873, and references therein). 
Compounds of formula (12-1) can be converted to compounds of formula (12-2) by, for example, but not limited to, hydroboration with a borane reagent, for example, B2H6-THF, 9-BBN (9-borabicyclo[3.3.1]nonane), and the like, (optionally complexed with THF, dimethylsulfide, phosphines, tertiary amines and the like) and followed by treatment with hydrogen peroxide and NaOH.
Compounds of formula (12-2) may be oxidized to compounds of formula (12-3) with a suitable oxidizing agent. Compounds of formula (12-3) can be reacted with appropriate substituted hydroxylamines of the general formula RONH2 where R is preferably R3, where R3 is as previously defined, in a protic solvent under acidic or basic conditions to give compounds of the formula (12-4). Representative acids include, but are not limited to, hydrochloric acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, etc. Representative bases include, for example, triethylamine, pyridine, diisopropylethyl amine, 1,5-lutidine, and the like. Appropriate solvents include, but are not limited to, methanol, ethanol, water, tetrahydrofuran, 1,2-dimethoxyethane and ethyl acetate.
Also, compounds of the formula (12-3), where the ketone is on the 6,11-4-carbon bridge, may be further derivatized, for example, but not limited to, conversion to the corresponding amines by reductive amination, reaction with hydrazines to form the corresponding hydrazones, conversion to substituted alkenes by Wittig reaction, alkylation with Grignard reagent etc., by standard methods known in the art and from references incorporated herein.